The proposed research project involves detailed characterization of whole genome variation in understudied ethnically and geographically diverse Africans living in distinct environments and with distinct diets. The dataset represents the most detailed catalog of genomic variation in under-represented African populations created to date. Population genetic analyses will enable us to identify potential functional variants that play a role in adaptation to diverse environments and to infer the demographic history of populations. Despite immense amounts of genetic variation and significant public health challenges, African human genetics has largely been understudied. It is important that recent advances in genomics and genetic medicine do not ignore Africa populations. Using high-coverage whole genome sequencing we will analyze whole genome sequences of multiple individuals in multiple African populations in order to infer both recent and ancient demographic history in Africa and to identify targets of natural selection in the human genome. Existing statistical population genetics approaches will be applied, and novel theoretical approaches will be developed to analyze population genomics datasets using a combination of computer simulations and mathematical modeling. Whole genome sequences will also be combined with data generated from genotyping arrays to assess the impact of SNP ascertainment bias on diverse African populations. Genomic variation present in African populations living in diverse climates and with diverse diets (agriculturalists, pastoralists and hunter- gatherers) is relevant o diseases of modernity, such as hypertension and diabetes. In addition, genetic variation found will be useful for genome-wide association studies of African populations. This proposed study is also highly relevant to the NIH's Human Heredity and Health in Africa Project (H3Africa), and this research project will contribute substantially to postdoctoral training. Finally, analytic approaches developed for African populations will also be useful to other studies that utilize next-generation sequencing technology. PUBLIC HEALTH RELEVANCE: This project is highly relevant to public health because African populations have substantial disease risks and African population genetics has largely been understudied. Sequencing the genomes of ethnically diverse African populations will greatly expand our knowledge of human genetic diversity and help identify genes of adaptive significance. The results of this study will be a powerful resource for understanding how genetic and environmental variation contributes to variable heritable traits and for designing and interpreting disease association studies.